WO2011127453A2 - Méthodes pour le diagnostic du cancer colorectal - Google Patents

Méthodes pour le diagnostic du cancer colorectal Download PDF

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WO2011127453A2
WO2011127453A2 PCT/US2011/031854 US2011031854W WO2011127453A2 WO 2011127453 A2 WO2011127453 A2 WO 2011127453A2 US 2011031854 W US2011031854 W US 2011031854W WO 2011127453 A2 WO2011127453 A2 WO 2011127453A2
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fap
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omvd
image
colorectal cancer
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WO2011127453A3 (fr
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Francis M. Giardiello
Daniel L. Edelstein
Jessica Ramella-Roman
Linda M. Hylind
Ali Basiri
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Johns Hopkins University
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Johns Hopkins University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7282—Event detection, e.g. detecting unique waveforms indicative of a medical condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
    • A61B5/0088—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for oral or dental tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222—Evaluating particular parts, e.g. particular organs
    • A61B5/4255—Intestines, colon or appendix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4887—Locating particular structures in or on the body
    • A61B5/489—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor

Definitions

  • the present invention relates generally to methods and systems for detecting the presence of or risk of developing cancer and more specifically to methods for detecting hereditary colorectal cancer (HCC), especially familial adenomatous polyposis (FAP).
  • HCC hereditary colorectal cancer
  • FAP familial adenomatous polyposis
  • Colorectal cancer also referred to as colon cancer or rectal cancer
  • colon cancer is a major American health problem.
  • Colorectal cancer includes any cancer in the colon from the beginning (at the cecum) to the end (at the rectum).
  • Colorectal cancer occurs when cells that line the colon (large bowel, large intestine) or the rectum (lower portion of the colon) become abnormal and grow out of control.
  • Polyps which are usually benign growths that protrude from a mucous membrane, can form in the colon and rectum. Such adenomatous polyps can eventually progress into cancer if left untreated.
  • colorectal cancers are sporadic, that is individuals developing such colorectal cancers have no prior family history of the disease. A number of different inherited conditions, however, can give rise to a significant risk of colon cancer. Individuals with a family history of colorectal cancer are described as having familial or hereditary colorectal cancer. It is estimated that 15% to 30% of colorectal cancers are familial. A single gene, a combination of genes, or a combination of genetic and environmental factors can cause familial colorectal cancer. Typically, such families have one or two members with a history of colorectal cancer or precancerous polyps.
  • a family is considered to have hereditary colorectal cancer when the exact gene that causes the disease is known.
  • Hereditary colorectal cancer HCC is thought to be among the most common of inherited human disorders with an estimated frequency of 1/500 individuals. About 3 to 5 % of those individuals afflicted with colorectal cancer have FAP or HNPCC. Others may have familial colorectal cancer (FCC).
  • FAP familial colorectal cancer
  • Familial adenomatous polyposis is a disorder that leads to hundreds, even thousands, of polyps in the colon and rectum at a young age, usually as a teenager or young adult.
  • FAP also is referred to as hereditary polyposis of the colorectum, familial polyposis, and Gardner's syndrome. It can progress to colorectal cancer in young adulthood if colectomy is not performed. This disorder is characterized by the development of hundreds of colorectal adenomas in adolescence. Bussey H.J.R., Familial polyposis coli. Family studies,
  • FAP is one of two well -described forms of HCC. The other is hereditary
  • HNPCC nonpolyposis colorectal cancer
  • Lynch syndrome or cancer family syndrome is a condition in which the tendency to develop colorectal cancer is inherited.
  • Individuals afflicted with HNPCC have a 50% chance of passing the HNPCC gene to each of their children.
  • patients afflicted with HCC or FCC are typically diagnosed by reviewing family history, i.e., identifying multiple members afflicted with colorectal cancer, and/or by molecular testing of the tissue or blood of patients suspected by clinical or family history characteristics to have this condition.
  • family history i.e., identifying multiple members afflicted with colorectal cancer
  • molecular testing of the tissue or blood of patients suspected by clinical or family history characteristics to have this condition.
  • the usual diagnosis of FCC HCC typically involves expensive molecular testing, which can cost from $750 to $3,000 with a mutation pickup rate of about 60%).
  • Such testing also can be lengthy. For example, it can take from about 6 weeks to about 10 weeks to obtain a result. This time-consuming process often interferes with proper treatment of patients afflicted with colorectal cancer who need medical decision making to be done expeditiously.
  • the presently disclosed subject matter is directed to methods and devices for using of phenotypic markers, especially oral mucosal vascular density (OMVD), for diagnosing colorectal cancer or an increased risk of colorectal cancer in a subject, especially FAP.
  • OMVD oral mucosal vascular density
  • the presently disclosed subject matter is directed to methods and devices for differentiating between FAP and HNPCC in subjects having or at risk of having HCC.
  • the presently disclosed subject matter is directed to methods and devices for differentiating between FAP and FCC in subjects having or at risk of having colorectal cancer.
  • the oral mucosal reflectance of a subject identified as a probable risk for FAP can be screened as a confirmation that it, rather than HPNCC, is likely present.
  • the invention provides an apparatus for measuring the oral vascular density in a subject.
  • the invention provides a method to monitor changes in vascular density over time; e.g.. responses over the course of cancer treatment, such as anti-angiogenic therapy.
  • the present invention provides a kit for measuring the oral vascular density in a subject.
  • the kit includes reagents for performing the measurements.
  • the kit can also include instructions on using kit components to identify an increased risk of developing FAP.
  • FIG. 1 is a schematic of an image capture and analysis system useful in the invention.
  • FIG. 2 is a scatter plot showing the values for oral mucosal vascular density measured in individuals afflicted with familial adenomatous polyposis (FAP) and controls.
  • FAP familial adenomatous polyposis
  • FIG. 3 is a scatter plot showing the values for oral mucosa reflectance measured in individuals afflicted with familial adenomatous polyposis (FAP) and controls.
  • FAP familial adenomatous polyposis
  • FIG. 4 shows receiver operator characteristic (ROC) curves for oral mucosal vascular density for familial adenomatous polyposis (FAP) patients over a range of cutoff points, indicative of the sensitivity and specificity provided by the FAP test of the invention.
  • ROC receiver operator characteristic
  • FIG. 5 shows the age relationship between measured OMVD values (scale of 10-6) and patient age in control subjects (o), FAP positive ( ⁇ )and FAP negative (+) patients.
  • FIG. 6 shows the ratio (R2 at 650 nm wavelength /Rl at 550 nm) of OMR values in control subjects (o), FAP positive ( ⁇ ) and FAP negative (+) patients.
  • embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1 %, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1 % from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • the term "about" when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth.
  • the recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1 , 2, 3, 4, and 5, as well as fractions thereof, e.g., 1 .5, 2.25, 3.75, 4.1 , and the like) and any range within that range.
  • OMR oral mucosal reflectance
  • the invention may also be used in conjunction with other diagnostic modalities for colorectal cancer; e.g., colonoscopy.
  • FAP in particular, several other phenotypic markers have been identified, albeit ones identifiable through invasive assay techniques, such as biopsy and subsequent laboratory examination, with lower efficacy rates than may be obtained through use of the invention.
  • phenotypic markers include occult radio-opaque jaw lesions, which are small, usually multiple, well circumscribed radiodensities detected by panoramic x-rays in the premolar and molar regions of the mandible and maxilla. See
  • a second phenotypic marker is congenital hypertrophy of the retinal pigment epithelium (CHRPE). These are discrete, round to oval, darkly pigmented retinal lesions ranging from 0.1 to 1 .0 optic disc diameters in size detected by indirect ophthalmoscopy. See Bosman et al., WHO Classification of Tumours of the Digestive System, 4th edition (2009); Traboulsi et al., "Pigmented ocular fundus lesions: Prevalence and significance in Gardner syndrome," N. Engl. J. Med. 316:661 667 (1987).
  • CHRPE retinal pigment epithelium
  • the efficacy of either CHRPE or occult radio-opaque jaw lesions for identifying patients afflicted with FAP is 70% and 67%, respectively, and 80% when both markers are used in combination. See Giardiello et al., "The value of combined phenotypic markers in identifying inheritance of familial adenomatous polyposis," Gut 32: 1 170-4 (1991 ).
  • the invention provides a test for FAP with efficacy greater than 80% and up to 90%.
  • the OMR of a subject identified as a probable risk for FAP can be screened as a confirmation that it, rather than HPNCC, is likely present.
  • a method according to the present invention can be performed during routine clinical care, for example as part of a general regular checkup, on a subject having no apparent or suspected neoplasm such as cancer. Therefore, the present invention in certain
  • inventions provides a screening method for the general population.
  • the methods of the present invention can be performed at a younger age than present cancer screening assays, for example where the method can be performed on a subject under 65, 55, 50, 40, 35, 30, 25, or 20 years of age.
  • the subject is typically a human but also can be any mammalian organism, including, but not limited to, a dog, cat, rabbit, cow, bird, rat, horse, pig, or monkey.
  • the method is performed as part of a regular checkup. Therefore, for these methods the subject has not been diagnosed with cancer, and typically for these present embodiments it. is not known that a subject has a colorectal cancer.
  • the risk of having cancer is then assessed by comparing the measured values to a known relationship between the OMVD present and the probability of the presence of the particular type of cancer, especially FAP.
  • a known relationship may be identified, as illustrated in the Examples, by determining OVMD meaurements in a statistically meaningful manner for FAP patients, and determining the OVMD measurements in a statistically meaningful manner in patients without cancer, and then calculating an odds ratio as a function of the measurements at which FAP is stastistically likely to be present or develop.
  • FIG. 1 An exemplary imager system 10 for use in performing the OVMD measurements of the invention (which may also be employed for OMR measurement) is schematically shown in Fig. 1 . Briefly, the system includes a chin rest 1 1.
  • a stabilizer tube 12 a stabilizer tube 12, a light source 13 (preferably mounted with a polarizing filter 14 and magnifying optics (not shown)), a pressure sensor 15, a tunable filter 16, a detector device (e.g., camera) 17 connected to a microscope 18 with illuminator 19 capable of recording an image of light reflected from the subject; and, a numerical analysis calculation program provided on a computer system 20 for calculating of a mucosal vascular density from a selected portion of the image by tracing each vessel in the mucosa with an automatic tracing algorithm.
  • a numerical analysis calculation program provided on a computer system 20 for calculating of a mucosal vascular density from a selected portion of the image by tracing each vessel in the mucosa with an automatic tracing algorithm.
  • the liquid crystal tunable filter (LCTF) 16 is commercially available; e.g., from VariSpec LCTF, Cambridge Research and Instrumentation, Inc., Woburn, MA..
  • the LCTF 16 has an operational range of 400 to 720 run in the visible spectrum with a 7 nm bandwidth and utilizes electronically controlled liquid crystal elements to select a transmitted wavelength range while blocking all others. This fine resolution allows for the precise isolation of individual wavelengths, providing a rapid, vibrationless selection of any wavelength in the visible to Near Infrared (NIR) range (470 to 700 nm).
  • the LCTF 16 may be used to record reflected light at increments of 5 nm within a range of 500 nm to 700 nm.
  • Camera 17 e.g., the 8 bit scientific camera available from Lumenera Corp., Ottawa, ON, Canada
  • a stereo microscope 18 captures magnifies images at a frame rate of 30 fps with a size of 1392 x 1040 pixels.
  • Other suitable image capture devices for use in the invention are commercially available; e.g., CCD or CMOS digital cameras used for microscopy (such as the INFINITY® line of cameras available from Lumenera Corp., Ottawa, ON, Canada).
  • a camera compatible for use with the MATLAB® analysis program e.g., a MATLAB® camera, Mathworks, Natick, MA.
  • images captured can be saved for analysis using the MATLAB® program, described further below.
  • Camera 1 7 is connected to microscope 18; e.g., through an eye-piece optical adaptor with a ring illuminator (Newport, Irvine, CA) 19 positioned in the acquisition side of the microscope assembly.
  • Polarized filter sheet 14 e.g., as available through Edmund Optics, Barrington, NJ
  • Such cross-polarization imaging not only eliminates specular reflection from the first interface but also minimizes the acquisition of single scattering photons remitted by the superficial tissue. Only photons that have undergone multiple scattering events are allowed back through polarizer 14 to camera 17. Some of these photons will travel through the superficial vasculature on their way back to imager system 10 in a process of
  • the detector and the numerical analysis program are preferably in electronic communication for automatic transmission of the image data from the detector to the program.
  • the image acquisition and data analysis may be conveniently automated.
  • Images obtained on imager system 10 are transmitted to computer 20 (along line A- A on Fig. 1 ) and stored for later analysis.
  • the analysis can be preformed through use of commercially available numerical analysis software programs, such as
  • MATLAB® Mathworks, Natick, MA.
  • other programs from Mathematica, Maple, IDLTM by ITT Visual Information Solutions and Metlynx as well as open source programs such as GNU OctaveTM, FreeMatTM, and ScilabTM.
  • the system provides OVMD values with a sensitivity and specificity (efficacy) at or above 80% and up to 90%.
  • An alternative system wherein the vessel tracing is performed manually may also be employed with efficacy lower than the system having an automatic tracing program, but still at or above 80%.
  • images are acquired from the inside of each patient's lip (conveniently, the lower lip).
  • Individual images may be acquired in an exposure time of as little as 250 milliseconds (ms) or longer, with a constant focal length.
  • Multiple images are preferably obtained for one or more sets of images to be used in analysis; e.g., from 1 to 120 images per set. preferably between 100 and 120 images per set, with each such set being obtained within a timeframe of 5 to 60 seconds; for example, between 10 and 50 seconds, 15 and 45 seconds, 20 and 40 seconds, or 25 to 30 seconds. Patients may relax their lips between acquisition of image sets.
  • images are obtained with the patient's chin positioned inside the chin holder 1 1 of an image capture device 10.
  • the patient manually pulls their lower lip downward using both hands over a stabilizer apparatus 12 positioned perpendicular to the chin rest while remaining as still as possible, or the position can be mechanically manipulated (e.g., using forceps).
  • An imaging field of about 1 cm in diameter is sufficient, although larger imaging samples of 1 .25, 1.5, 1 .75 and 2 cm may also be utilized.
  • Images are obtained in the near infrared spectrum of between 470 and 700 nm, preferably between 500 and 700 nm, or 550 and 700 nm, or 575 nm and 700, or at 550 nm, or at 650 nm.
  • multiple images are obtained at multiple wavelengths, starting at an initial wavelength of about 500 nm and increasing in increments of about 5 nm to a final wavelength of about 700 nm.
  • each image e.g., a 300 * 600 pixel section is sufficient for use with the MATLAB® analysis program
  • each vessel in the image traced using a suitable automatic tracing program or by manual measurement.
  • the automatic tracing algorithm disclosed in Sofka M. and Stewart C.V. "Retinal vessel centerline extraction using multiscale matched filters, confidence and edge measures," IEEE Transactions on Medical Imaging 25: 1531 -1546 (2006) may be employed.
  • a binary map of the traced vessels is generated for analysis.
  • an algorithm quantifying the Kolmogorov Complexity of traced images may be employed to calculate an oral vascular density score for each subject (see Kaspar F., and Schuster H.G., "Easily calculable measure for the complexity of spatiotemporal patterns," Physical Review A 36:842 (2005)).
  • Use of an extended template of a multiscale matched filter helps to preserve vessels that are only a pixel wide and usually low contrast with respect to background in images.
  • OMVD values compared to control values are considered to be diagnostic for FAP.
  • Patients afflicted with FAP are those with statistically significantly increased oral mucosal vascular density compared to controls.
  • the analysis will ideally account for differences in demographic characteristics between subjects with FAP and controls, using a two-tailed unpaired Student's t test. A probability of P ⁇ 0.05 is considered to be statistically significant for these purposes.
  • a difference between vascular density measured in controls versus FAP sufferers which is "diagnostically significant" may be between 5 and 15% (or greater), or between 10 and 15% or greater.
  • a vascular density score (p ⁇ 0.001 ) calculated by quantifying the Kolmogorov Complexity of traced images (further detailed in the Examples) at about 0.23 on average in controls, whereas the scores in FAP sufferers averaged around 0.27, an approximately 15% increase over the control values.
  • the sensitivity and specificity (collectively, efficacy) of oral mucosal vascular density for FAP determined according to the invention are 90% and 90%, respectively, at a OMVD cut off level of 0.2731 (see, Fig. 4).
  • Sensitivity for FAP is defined as the percentage of affected patients with a positive test (true positives divided by true positives and false negatives expressed as a percentage).
  • Specificity is defined as the percentage of unaffected subjects with a negative test (true negatives divided by true negatives and false positives expressed as a percentage).
  • the predictive value of a positive test is defined as the percentage of subjects with a positive test who had FAP (true positives divided by true positives and false negatives expressed as a percentage).
  • the predictive value of a negative test is defined as the percentage of subjects with a negative test who did not have diagnosed FAP (true positives divided by true positives and false negatives expressed as a percentage).
  • the efficiency of the test is defined as the percentage of all subjects correctly classified (true positives and false positives divided by true negatives and false negatives, expressed as a percentage).
  • OMR measurements may also be performed; e.g., through application of the OMR measurement protocol described in DeFelice, et al., Gut, 52: 1764- 1767, 2003;
  • OMR optical magnetic resonance
  • phenotypic markers may be evaluated as elsewhere described hereinabove. Those of ordinary skill in the art will be familiar with or can readily ascertain means for performing such analyses.
  • vascular density may occur both as the disease progresses or as it is ameliorated through therapy.
  • vascular density increases that occurred as a consequence of FAP may be wholly or partially ameliorated or controlled through anti-angiogenic therapy.
  • an OMVD value obtained in a FAP subject is compared to a later OMVD value from the same subject.
  • An increase, decrease or no difference between the OMVD values is informative regarding the progression of the disease or response to therapy therefor by the subject.
  • Such values may be measured at clinically indicated points over time to monitor the progression of the disease or response to therapy, with such measurements being obtained through practice of the invention.
  • Kits may be provided for use of the invention which include instructions for performing the OMVD measurements as well as suggestions for confirmatory analyses, such as measurement of OMR to exclude HNPCC as a diagnosis as well as other conventional tests, such as colonoscopy.
  • Optical filters for the image capture device together with instructions for its use would be optionally provided for users who do not have, or may need to replenish, supplies of these items.
  • a copy of or instructions for access to a preloaded version of a numerical analysis program, together with instructions for its use, may also be provided.
  • Additional components may include chin rest covers and forceps or other devices for securing the lip into a suitable position for imaging.
  • FIG. 1 A schematic of an image capture and analysis device useful in the invention is provided in Fig. 1.
  • a device was assembled consisting of a scientific camera (Lumenera Corp., Ottawa, ON, Canada), imaging optics, a computer, and a liquid crystal tunable filter (LCTF), (VariSpec LCTF, Cambridge Research and Instrumentation, Inc., Woburn, MA).
  • LCTF liquid crystal tunable filter
  • the LCTF has an operational range of 400 to 720 nm in the visible spectrum with a 7 nm bandwidth and utilizes electronically controlled liquid crystal elements to select a transmitted wavelength range while blocking all others. This fine resolution allows for the precise isolation of individual wavelengths, providing a rapid, vibrationless selection of any wavelength in the visible to Near Infrared (NIK) range (470 to 700 nm).
  • the LCTF records reflectance at increments of 5 nm within a range of 500 nm to 700 nm.
  • An 8 bit Lumenera camera mounted to a stereo microscope captured magnified images at a frame rate of 30 fps with a size of 1392 x 1040 pixels.
  • the camera was connected to the microscope through an eye-piece optical adaptor, with a ring illuminator (Newport, Irvine, CA) positioned in the acquisition side of the microscope assembly.
  • a polarized sheet (Edmund Optics, Barrington, NJ) was positioned in front of the light source and aligned perpendicularly to the LCTF to eliminate specular reflection.
  • Test subjects were asked to hold their lower lip in a downward position with both hands as the imaging device was aligned to their lower lip.
  • the focal length of the camera remained identical for each subject in order to insure consistency of the imaged area of oral mucosa between patients. Patient movement was largely eliminated through the use of a chin rest, which stabi lized the subject in a standardized position.
  • the acquisition and analysis of the data was conducted in MATLAB® on a Pentium 4 laptop (Hewlett Packard® Pavilion).
  • OMR was determined in the subjects as well as OMVD. It has been reported that a higher reflectance (above 625 nm) occurs in control subjects than those positive for HNPCC, whereas reflectance below 57.5 nm was the same for both populations. Thus, the subjects were evaluated by calculating the ratio of reflectance at two wavelengths, 550 nm and 650 nm (R2 and Rl , as shown in Fig. 6).
  • the oral mucosal vascular density was calculated from a 300 x 600 pixel portion of the main image manually selected by the operator. Each vessel in the image was traced using an automatic tracing algorithm by Sofka and Steward. See Sofka M.
  • the oral mucosal reflectance was also calculated from the same 300 x 600 pixel portion of the main image. The average value of all pixels was calculated, and this value corresponded to the total normal reflectance.
  • the confidence measure emphasizes the shape of the intensity surface, which helps detect low contrast vessels.
  • the vessel boundary is useful in distinguishing between offset edges near tissue abnormalities and true vessels. Normalized images were input as data into the vessel tracing algorithm.
  • the Kolmogorov Complexity of each image was calculated using an algorithm to quantify the degree of OMVD in each binary image (representative data are shown in Fig. 2).
  • the amount of pressure exerted on the lip during measurement was initially thought to cause local ischemia, potentially interfering with the accuracy of vessel tracing.
  • a pressure sensor (Phidgets, Calgary, Alberta, Canada) was embedded on the spacer and connected to a data acquisition card and monitor unit (Fluke 189 RMS multimeter, Everett, WA, USA) ultimately proving to be unimportant in the final measurement.
  • OMVD measurements obtained in the patients evidenced a statistically significant increase in the OMVD of the former group compared to the latter (Fig. 2).
  • OMR measurements obtained in the patients showed no statistically significant difference between controls and FAP sufferers (see, Fig. 3).
  • Sensitivity for FAP was defined as the percentage of affected patients with a positive test (true positives divided by true positives and false negatives expressed as a percentage). Specificity was defined as the percentage of unaffected subjects with a negative test (true negatives divided by true negatives and false positives expressed as a percentage). Predictive value of a positive test was defined as the percentage of subjects with a positive test who had FAP (true positives divided by true positives and false positives expressed as a percentage). Predictive value of a negative test was defined as the percentage of subjects with a negative test who did not have polyposis (true negatives divided by false negatives and true negatives expressed as a percentage).
  • Efficiency of the test was defined as the percentage of all subjects correctly classified (true positives and true negatives divided by true positives and false positives and true negatives and false negatives, expressed as a percentage).
  • the results obtained show that patients afflicted with familial adenomatous polyposis had statistically significantly increased oral mucosal vascular density compared to controls (p ⁇ 0.001 ).
  • the sensitivity and specificity of oral mucosal vascular density for FAP was 90% and 90%, respectively. No association between this marker and age or gender was noted (see, e.g., Fig. 5 as to patient age).
  • the positive and negative predictive values for oral mucosal vascular density for FAP were 84% and 94%, respectively.
  • OMR total diffused oral mucosal reflectance
  • OMVD oral mucosal vascular density
  • OMVD is an efficient test for familial adenomatous polyposis which offers a higher level of specificity and sensitivity than available tests or combinations of tests for FAP. It can be performed quickly and non-invasively.
  • the test is readily susceptible to automation.

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Abstract

La présente invention a pour objet des méthodes et des systèmes pour l'utilisation de marqueurs phénotypiques, principalement de la densité vasculaire des muqueuses buccales seule ou en combinaison avec la détection d'autres marqueurs, pour identifier des individus atteints ou présentant un risque accru de cancer colorectal héréditaire, en particulier de polypose adénomateuse familiale.
PCT/US2011/031854 2010-04-08 2011-04-08 Méthodes pour le diagnostic du cancer colorectal Ceased WO2011127453A2 (fr)

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